title: NOTCH3 variants and risk of ischemic stroke.
abstract: BACKGROUND
  Mutations within the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL mutations appear to be restricted to the first twenty-four exons, resulting in the gain or loss of a cysteine amino acid. The role of other exonic NOTCH3 variation not involving cysteine residues and mutations in exons 25-33 in ischemic stroke remains unresolved.
  
  
  METHODS
  All 33 exons of NOTCH3 were sequenced in 269 Caucasian probands from the Siblings With Ischemic Stroke Study (SWISS), a 70-center North American affected sibling pair study and 95 healthy Caucasian control subjects. Variants identified by sequencing in the SWISS probands were then tested for association with ischemic stroke using US Caucasian controls collected at the Mayo Clinic (n=654), and further assessed in a Caucasian (n=802) and African American (n=298) patient-control series collected through the Ischemic Stroke Genetics Study (ISGS).
  
  
  RESULTS
  Sequencing of the 269 SWISS probands identified one (0.4%) with small vessel type stroke carrying a known CADASIL mutation (p.R558C; Exon 11). Of the 19 common NOTCH3 variants identified, the only variant significantly associated with ischemic stroke after multiple testing adjustment was p.R1560P (rs78501403; Exon 25) in the combined SWISS and ISGS Caucasian series (Odds Ratio [OR] 0.50, P=0.0022) where presence of the minor allele was protective against ischemic stroke. Although only significant prior to adjustment for multiple testing, p.T101T (rs3815188; Exon 3) was associated with an increased risk of small-vessel stroke (OR: 1.56, P=0.008) and p.P380P (rs61749020; Exon 7) was associated with decreased risk of large-vessel stroke (OR: 0.35, P=0.047) in Caucasians. No significant associations were observed in the small African American series.
  
  
  CONCLUSIONS
  Cysteine-affecting NOTCH3 mutations are rare in patients with typical ischemic stroke, however our observation that common NOTCH3 variants may be associated with risk of ischemic stroke warrants further study.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America.
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.forename: Alexandra I
authors.initials: AI
authors.lastname: Soto-Ortolaza
authors.forename: Michael G
authors.initials: MG
authors.lastname: Heckman
authors.forename: Christophe
authors.initials: C
authors.lastname: Verbeeck
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Serie
authors.forename: Sruti
authors.initials: S
authors.lastname: Rayaprolu
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalls
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.forename: Rita
authors.initials: R
authors.lastname: Guerreiro
authors.forename: Emma
authors.initials: E
authors.lastname: Kinsella
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Brott
authors.forename: Robert D
authors.initials: RD
authors.lastname: Brown
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Worrall
authors.forename: James F
authors.initials: JF
authors.lastname: Meschia
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia / Q000150:complications* / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics*; D012307:Risk Factors; D020521:Stroke / Q000150:complications* / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch